Abstractfibroblasts, and that the thickness of the subepithelial collagen appears to be Background -Bronchial asthma is charlinked to an increase in bronchial reacterised by airway structural changes, insponsiveness and exacerbation of clinical cluding mucosal inflammatory infiltration manifestations. and subepithelial collagen deposition, that (Thorax 1998;53:21-27) may represent the morphological basis for the chronicity of the disease. The relationship between airway wall thickness Keywords: bronchial asthma, growth factors, fibroblast, remodelling of airway wall.and growth factors in asthma has not been elucidated. Methods -Bronchial biopsy specimens were obtained from 21 asthmatic patients Identification of the histopathological features and eight healthy subjects and the base-of bronchial asthma has been largely based ment membrane thickness was measured on the results of necropsy studies which have by light microscopy and electron micro-documented epithelial cell shedding, inflamscopy. At the same time the numbers of matory cell infiltrate with numerous eosinoeosinophils and fibroblasts were assessed phils, 1 2 and subepithelial collagen thickening. and the expression of transforming growth It has now become clear that this phenomenon factor 1 (TGF-1 ), platelet derived growth occurs in mild atopic asthma, even in patients factor (PDGF), and insulin like growth with a relatively short clinical history.3 In factor (IGF) I in the bronchial mucosa patients with asthma chronic inflammation dewas examined by immunostaining. The termines pathological changes in the airways relationship between the degree of thick-and causes marked remodelling of the structure ening of the subepithelial layer and both of the bronchi. 4 Bronchial biopsy specimens the clinical data and pulmonary function from asthmatic patients have indicated that the were also investigated.typical remodelling of the airways is caused by Results -The basement membrane of the thickening of the subepithelial layer.5 This view asthmatic patients was thicker than that has persisted, despite ultrastructural studies of the healthy controls (median 8.09 versus showing that the true epithelial basement mem-4.02 m). Electron microscopic examina-brane was normal and that the thickening was tion of the basement membrane revealed due to deposition of fibrillar collagen species, thickening of the subepithelial lamina re-leading to an increase in depth and density of ticularis; this thickening significantly cor-the lamina reticularis beneath the basement related with the number of fibroblasts in membrane.6 7 Further studies using antibodies the submucosa in the asthmatic subjects to different types of collagen have revealed an (r S =0.88) but not in the controls (r S =0.70). increase in the amount of interstitial collagen There was a significantly higher number of types I, III, and V and fibronectin in the eosinophils in the airways of the asthmatic thickened basal lamina of patients with subjects than in the healthy subjects asthma. histochemistry. Further...
Eosinophil differentiation occurs within the bone marrow in response to eosinopoietic cytokines, particularly IL-5. Recently, however, eosinophil precursors (CD34/IL-5Rα+ cells) and IL-5 mRNA+ cells have been identified within the lungs of asthmatics, indicating that a population of eosinophils may differentiate in situ. In this report, we examined the presence of eosinophil precursors within allergic nasal mucosa and examined whether they undergo local differentiation following ex vivo stimulation. We cultured human nasal mucosa obtained from individuals with seasonal allergic rhinitis with either specific allergen, recombinant human IL-5 (rhIL-5), or allergen + soluble IL-5Rα (sIL-5Rα), shown to antagonize IL-5 function. Simultaneous immunocytochemistry and in situ hybridization demonstrated that there were fewer cells coexpressing CD34 immunoreactivity and IL-5Rα mRNA following culture with allergen or rhIL-5, compared with medium alone. Immunostaining revealed that the number of major basic protein (MBP) immunoreactive cells (eosinophils) was higher within tissue stimulated with allergen or rhIL-5, compared with unstimulated tissue. In situ hybridization detected an increase in IL-5 mRNA+ cells in sections from tissue cultured with allergen, compared with medium alone. These effects were not observed in tissue cultured with a combination of allergen and sIL-5Rα. Colocalization analysis indicated this expression to be mainly, but not exclusively, T cell (44%) and eosinophil (10%) derived. Our findings suggest that a subset of eosinophils may differentiate locally within allergic nasal mucosa, in what appears to be a highly IL-5-dependent fashion, and imply that this process might be regulated in vivo by endogenous production of sIL-5Rα.
P-glycoprotein (P-gp, ABCB1, MDR1) was recognized as a drug-exporting protein from cancer cells three decade ago. Apart from the multidrug transporter side effects of P-gp, normal physiological functions of P-gp have been reported. P-gp could be responsible for translocating platelet-activating factor (PAF) across the plasma membrane and PAF inhibited drug transport mediated by P-gp in cancer cells. P-gp regulated the translocation of sphingomyelin (SM) and GlcCer, and short chain C(6)-NBD-GlcCer was found in the apical medium of P-gp cells exclusively and not in the basolateral membrane. SM plays an important role in the esterification of cholesterol. High expression of P-gp prevents stem-cell differentiation, leading to the proliferation and amplification of this cell repertoire, and functional P-gp plays a fundamental role in regulating programmed cell death, apoptosis. The transporter function of P-gp is therefore necessary to protect cells from death. P-gp can translocate both C(6)-NBD-PC and C(6)-NBD-PE across the apical membrane. This PC translocation was also confirmed with [(3)H]choline radioactivity. Progesterone is not transported by P-gp, but blocks P-gp-mediated efflux of other drugs and P-gp can mediate the transport of a variety of steroids. Cells transfected with human P-gp esterified more cholesterol. P-gp might also be involved in the transport of cytokines, particularly IL-1beta, IL-2, IL-4 and IFNgamma, out of activated normal lymphocytes into the surrounding medium. P-gp expression is also associated with a volume-activated chloride channel, thus P-gp is bifunctional with both transport and channel regulators. We also present information about P-gp polymorphism and new structural concepts, "gate" and "twist", of the P-gp structure.
Voltage clamp analyses, combined with pharmacological tools demonstrate the independence of reactive Na and K channels in electrically excitable membrane of eel electroplaques. Spike electrogenesis is due to Na activation and is eliminated by tetrodotoxin or mussel poison, or by substituting choline, K, Cs, or Rb for Na in the medium. The K channels remain reactive, but K activation is always absent, the electroplaques responding only with K inactivation. This is indicated by an increased resistance when the membrane is depolarized by more than about 30 mv. The resting resistance (1 to 5 ohm cm 2 ) is dependent upon the ionic conditions, but when K inactivation occurs the resistance becomes about 10 ohm cm 2 in all conditions. K inactivation does not change the EMF significantly. The transition from low to high resistance may give rise to a negative-slope voltage current characteristic, and to regenerative inactivation responses under current clamp. The further demonstration that pharmacological K inactivation (by Cs or Rb) leaves Na activation and spike electrogenesis unaffected emphasizes the independence of the reactive processes and suggests different chemical compositions for the membrane structures through which they operate.An observation by Altamirano (1955) implied that the intracellularly recorded spikes of eel electroplaques differ from the conductile responses of most other cells. The resistance of the electrogenically reactive caudal membrane of the electroplaques increased two-to threefold over the resting value when this membrane was depolarized by applied currents which exceeded a certain threshold. The increase was evident during the falling phase of the spikes which were elicited by the applied currents and it persisted as long as the current pulses were applied (ca. 20 msec.). The resistance increase also
For robots to coexist with humans in a social world like ours, it is crucial that they possess human-like social interaction skills. Programming a robot to possess such skills is a challenging task. In this paper, we propose a Multimodal Deep Q-Network (MDQN) to enable a robot to learn human-like interaction skills through a trial and error method. This paper aims to develop a robot that gathers data during its interaction with a human, and learns human interaction behavior from the high dimensional sensory information using end-to-end reinforcement learning. This paper demonstrates that the robot was able to learn basic interaction skills successfully, after 14 days of interacting with people.
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